Sepsis is one of the top leading causes of deaths for Americans and it is responsible for approximately 200,000 deaths in US annually. Despite of the advance of antibiotics and medical treatment in general, there has been no reduction in severity and death associated with the disease. Since inflammation is the underlying cause of sepsis, the lack of progress in sepsis treatment suggests major gaps in understanding the root cause of inflammation associated with infection. A major breakthrough in immunology is the identification of pathogen-associated molecular pattern (PAMP) as the root cause of inflammation. However, PAMP alone does not explain sepsis as controlling infection, which should remove PAMP, is insufficient to cure sepsis. Another source of inflammation is tissue damage-associated molecular pattern (DAMP). We have recently demonstrated that host response to DAMP is controlled by CD24-Siglec 10/G interaction. Our preliminary data provided herein demonstrated that sepsis is associated with disruption of CD24-Siglec 10 interaction and polybacterial sepsis in the mouse can be effectively treated by sialidase inhibitors. Here we propose to use rational drug design and a novel enzymo-chemical synthesis strategy to produce sialidase inhibitors for the treatment of sepsis, as detailed in two specific aims. Specifically, we will produce new sialidase inhibitors through the rational drug design and our novel enzymochemical strategy. Then we will use cecal ligation and puncture (CLP) model to test the therapeutic efficacy of the novel sialidase inhibitors. As proof of concept, the successful completion of this proposal will not only sustain bacterial sialidase as the therapeutic target for sepsis, but also provide new and effective prototype drugs for further development. PUBLIC HEALTH RELEVANCE: Sepsis is the tenth leading cause of deaths for Americans as it is responsible for approximately 200,000 deaths in US annually. Despite of the advance of antibiotics and medical treatment in general, there has been no reduction in severity and death associated with the disease. The ultimate goal of this application is to develop a novel and effective treatment for sepsis by targeting on the bacterial sialidase.